Patent GB-784615-A (GB)
Title: Diuretics comprising acylated aminotriazines
Inventor: CROWTHER ALBERT FREDERICK
IPC: A61K31/00
Filed: 1954-12-24
Abstract: The invention comprises mono- and di-acyl derivatives of compounds of the formula: <FORM:0784615/IV (a)/1> wherein Ar is an aryl radical which bears one or more halogen substituents, and of R and R1 one stands for hydrogen or a lower alkyl radical and the other stands for hydrogen, and the acyl groups are of the formula AlkCO-, AlkOCH2CO or Ar1CO or Ar1CH2CO, where "Alk" stands for an alkyl radical and Ar1 is an aryl radical which may optionally be substituted, e.g. by halogen atoms.  The compounds are made by acylating an amino-triazine of the formula 1, for example by treatment with a mixture of the appropriate acid and acid anhydride or, more especially in the case where it is desired to introduce two acyl groups, by treatment with an excess of the appropriate acid anhydride in the presence of a dehydrating agent such as sulphuric acid.  Acylation may also be effected by treatment with an acid chloride and a tertiary base such as pyridine or diethylaniline, optionally in the presence of an inert solvent or diluent such as dioxane or acetone.  Suitable acid chlorides include palmityl-, n-butyryl-, isobutyryl-, propionyl-, ethoxyacetyl-, n-valeryl-, n-caproyl-, n-caprylyl-, benzoyl-, p-chlorobenzoyl- and phenacetyl chloride.  A further process for the preparation of the monoacyl compounds comprises acylation of an alkali metal derivative, e.g. a sodium derivative, of a compound of the formula (I) with the appropriate acid chloride in an inert solvent or diluent such as dioxane.  The compounds may also be made by halogenation of corresponding acylated amino-triazine derivatives wherein the radical Ar is capable of further halogenation.  Preferred products include the mono-propionyl and mono-n-butyryl derivatives of 2-amine-4-(2 : 4 - dichloraniline) - 1 : 3 : 5 - triazine, the mono-ethoxyacetyl derivative of 2-isopropyl-amino - 4 - p - chloranilino - 1 : 3 : 5 - triazine and the mono-propionyl derivative of isopropylamino - 4 - (2 : 4 - dichloranilino) - 1 : 3 : 5-triazine.  Examples describe the preparation of mono or di acyl derivatives, e.g. acetyl-, propionyl-, palmityl-, isobutyryl-, ethoxyacetyl-, n-butyryl-, n-valeryl-, n-caproyl-, n-caprylyl-, n-capryl-, benzoyl-, p-chlorobenzoyl- and phenylacetyl derivatives, of 2 : 4-diaminotriazines of the general formula (I) wherein -NHR1 may be an amino or isopropyl amino group and the group -NRAr may be a p-chloranilino:, 2 : 4 - dichloronilino -, 2 : 5 - dichloranilino - or 3 : 5 - dichloranilino - group.  The products are used as diuretics.ALSO:Diuretic pharmaceutical compositions comprise mono- and di-acyl derivatives of triazine compounds of the formula <FORM:0784615/VI/1> wherein Ar is an aryl radical which bears one or more halogen substituents and, of R and R1, one stands for hydrogen or a lower alkyl radical and the other stands for hydrogen, together with known pharmaceutical excipients. Suitable compositions comprise tablets or pills containing between 5 per cent and 90 per cent of the active ingredient or ingredients, one or more diluents such as calcium carbonate or lactose, one or more disintegrating agents such as maize starch, one or more lubricating agents such as stearic acid or magnesium stearate and one or more granulating or binding agents such as starch paste, gelatine or gum acacia.  The pharmaceutical compositions may also take the form of aqueous dispersions wherein the excipients include one or more suspending or dispersing agents such as neutral hydrophilic colloids, for example sodium carboxymethyl cellulose, one or more wetting agents, for example a polyethyleneoxycetanol, one or more preservatives such as an ester of p-hydroxybenzoic acid, for example the methyl ester and colouring and/or flavouring agents.  Examples describe compositions comprising: (29) tablets containing the mono-propionyl derivative of 2-amino-4-(2 : 4-dichloroanilino)-1 : 3 : 5-triazine admixed with maize starch, calcium carbonate and magnesium stearate; (30) a suspension in water containing icing sugar, sodium carboxymethyl cellulose, heptadecaethyleneoxycetanol, methyl p - hydroxybenzoate, raspberry flavouring, edible dyestuff, and the mono-n-butyryl derivative of 2-amino-4-(2 : 4 - dichloroanilino) - 1 : 3 : 5 - triazine; (31) tablets containing the mono-ethoxyacetyl derivative of 2-isopropylamino-4-p-chloroaniline-1 : 3 : 5 - triazine, calcium carbonate, maize starch, maize starch paste and magnesium stearate; and (32) a suspension according to (30) containing in place of the mono-n-butyryl derivative of 2-amino-4-(2 : 4-dichloroanilino)-1 : 3 : 5-triazine, the mono-propionyl derivative of 2 - isopropyl - 4 - (2 : 4 - dichloroanilino)-1 : 3 : 5-triaze.